Shared CD4+ T cell receptor specificity groups in Crohn's disease and ulcerative colitis

Area of Science:

• Immunology
• Genetics
• Gastroenterology

Background:

• Inflammatory bowel disease (IBD), including ulcerative colitis (UC) and Crohn's disease (CD), is characterized by chronic gut inflammation and immune system dysfunction.
• Aberrant CD4+ memory T cell responses are common in both UC and CD, with HLA-DRB1 identified as a significant genetic risk factor.
• The precise mechanisms by which HLA-DRB1 genotypes influence T cell receptor (TCR) specificity in IBD are not fully understood.

Purpose of the Study:

• To investigate the relationship between HLA-DRB1 genotypes and TCR specificity in patients with IBD.
• To identify specific TCR repertoires associated with IBD and shared between UC and CD.
• To explore the functional implications of these TCR specificities in the context of IBD pathogenesis.

Main Methods:

• Genotyping of HLA-DRB1 alleles in IBD patients and healthy controls.
• Sequencing of T cell receptor beta (TCRb) chains from circulating memory CD4+ T cells.
• Bioinformatic analysis using the GLIPH2 algorithm to identify TCR specificity groups based on CDR3 amino acid motifs.

Main Results:

• Profiling of over 3.13 million TCRb sequences revealed 440 high-confidence TCR specificity groups.
• Five TCR specificity groups were significantly enriched in IBD patients and shared between UC and CD cohorts, suggesting common antigen targets.
• Increased frequencies of cytotoxic CD4+ and CD8+ T cells were observed in IBD patients carrying specific HLA-DRB1 risk alleles.

Conclusions:

• Distinct HLA-DRB1-associated TCR specificity groups are implicated in IBD pathogenesis.
• The findings suggest shared antigen targets in both UC and CD, mediated by specific T cell responses.
• This research provides mechanistic insights into IBD and may facilitate antigen discovery and personalized treatment strategies.